The lacrima is produced by the lacrimal gland located at an outer side of the eyelid, supplies moisture to the ocular surface, and is discharged from the lacrimal puncta, located in the inner corner of the eye, to the back of the nose. The lacrima form was said in the past to have a three-layer structure of the lipid layer, the aqueous layer, and the mucin layer on the ocular surface from the outer side to the cornea. In recent years, however, the concept which has become prevalent is that there is no partition between the aqueous layer and the mucin layer and mucins are mixed in the aqueous layer with a concentration gradient. Presently, the concept is that the ocular surface has a two-layer structure of the lipid layer and the aqueous layer having mucins mixed therein. Dry eye occurs if a problem arises in one of the two layers of this structure.
The “evaporative dry eye,” which occurs when a problem arises in the lipid layer of the lacrima, includes meibomian gland dysfunction and blepharitis. The “aqueous deficient dry eye,” which occurs when a problem arises in the aqueous layer of the lacrima, includes Sjögren's syndrome and the Stevens-Johnson syndrome.
In 2016, the Dry Eye Society defined that “Dry eye is a multifactorial disease of the tear film instability that results in symptoms of discomfort, visual disturbance and potential damage to the ocular surface.”
The ultimate purpose of dry eye treatment is to restore the lacrima form to the normal and to ameliorate keratoconjunctival epithelial disorder and subjective symptom.
Instillations actually used for the treatment of dry eye include aqueous ophthalmic solutions, including an artificial lacrima, sodium hyaluronate, chondroitin sulfate sodium, and flavin adenine dinucleotide, serum instillations, oil instillation, and the like. In recent years, therapeutic agents for dry eyes such as diquafosol sodium and rebamipide are commercially available. In the case of a mild degree of dry eye, OTC ophthalmic drugs as an artificial lacrima having an efficacy and effect of supplying the lacrima (drying of eye) are easily available in Japan.
The role of an artificial lacrima is a method of increasing the lacrima by supplying deficient lacrima from the outside. The amount of lacrima has reported to be 6.5±0.3 μL for an ordinary person and 4.8±0.4 μL for a dry eye patient, the capacity of the conjunctival sac is 20 to 30 μL, and one drop of ophthalmic solution is about 50 μL. Thus, if one drop of artificial lacrima is instilled to one eye, the conjunctival sac is filled with water in the cases of both an ordinary person and a dry eye patient.
An artificial lacrima is, for example, an aqueous ophthalmic solution added with inorganic salts. However, after instillation, a phenomenon takes place in which such an aqueous ophthalmic solution is rapidly discharged through the nasolacrimal duct or evaporates from the ocular surface. Thus, for the purpose of maintaining moisture on the ocular surface or mitigating subjective symptoms, frequent instillation is required, for example 2 or 3 drops at a time and 5 or 6 times per day (Non Patent Literatures 1 to 3).
Ophthalmic solutions are commercially available which are blended with a water soluble polymer to obtain a high viscosity for the purpose of delaying such discharge of an artificial lacrima from the ocular surface and further supplying a large amount of water. As the water soluble polymer, for example, hypromellose (HPMC), hydroxyethyl cellulose (HEC), or hyaluronic acid and a pharmaceutically acceptable salt thereof are added as a thickening agent. However, it is known that such an ophthalmic solution is high in viscosity and thus it is difficult to adjust the amount added dropwise at the time of application and that discomfort such as blurred vision after instillation is caused.
It is known that among the water soluble polymers, methyl cellulose being a cellulose derivative is a cornea surface layer protection agent, and 0.5% methyl cellulose -containing physiological saline provides water retainability to the surface of the cornea, forming a thin film having properties similar to those of the lacrima (Non Patent Literature 4).
In addition, it is known that 0.6% and 1.2% methyl cellulose-containing physiological salines provided a therapeutic effect for a wound in the corneal epithelium of a pig eyeball (Non Patent Literature 5).
However, in these methyl cellulose-containing physiological salines, the property of forming into gel due to heat, which is specific to methyl cellulose, was not observed on the solution. The effects by gelation are not considered at all.
As an aqueous pharmaceutical composition containing methyl cellulose, it is described that a thermo-responsive gelling formulation which contains methyl cellulose, and hyaluronic acid and pharmaceutically acceptable salts thereof or a thermo-responsive gelling artificial lacrima which contains methyl cellulose, MACROGOL 4000, and sodium citrate is used for the purpose of increasing the amount of lacrima by gelation around the body temperature, supplying water to the ocular surface, and protecting the lipid layer of the lacrima (Patent Literatures 1 and 2).
On the other hand, a thermo-responsive gelling aqueous pharmaceutical composition is disclosed which contains a new quinolone-based antibacterial agent as an active ingredient and which has a sufficiently low gelling temperature. In addition, as the composition mentioned above, an ofloxacin gel forming ophthalmic solution 0.3% “WAKAMOTO” is reported to have an effect for conical epithelial disorders (Patent Literature 3 and Non Patent Literature 6).
The foregoing only describes an effect of a gel forming ophthalmic solution containing one type of methyl cellulose in a gel forming ophthalmic solution containing an antibacterial agent. The above aqueous pharmaceutical compositions disclosed in these Patent Literatures are usually assumed to be stored at low temperatures because, if stored at room temperature, the composition gradually forms into gel and a characteristic of being easily applied in the form of liquid before instillation is lost. Although frequent instillation is generally carried out in the case of an artificial lacrima as described above, the reversible thermo-responsive gelling aqueous composition is inappropriate to carry with because it needs to be stored at low temperatures.
As an aqueous pharmaceutical composition containing any of methyl cellulose, polyethylene glycol, and sodium citrate, sugar alcohol, lactose, carmellose, and cyclodextrin, disclosed is a composition which, even if formed into gel at room temperature, rapidly decreases in viscosity and transforms back to liquid when a weak force is applied thereto, such as when the aqueous pharmaceutical composition is shook gently. In other words, an aqueous composition having thixotropy is disclosed (Patent Literature 4).
Regarding an aqueous composition which is made up of an aqueous solution containing hydroxyethyl cellulose, methyl cellulose, or hypromellose, disclosed is a composition which does not rapidly increase viscosity around the human body temperature to form a gel but rapidly decreases in viscosity and increases in fluidity when a weak force is applied such as when the aqueous composition is shook gently (Patent Literature 5).
As described above, with focus on distribution of products and on QOL, improvements have been carried out, including portable thermo-responsive gelling formulations and aqueous compositions which do not produce a feeling of foreign matter after application. However, an aqueous composition which achieves thixotropy by repetition of sol-gel phase transitions is not disclosed.
As described above, an aqueous composition made by combining methyl celluloses with different standards at a particular ratio is not known at all which forms into gel around the body temperature but transitions to sol when a physical stimulus is applied and which exhibits reproducibility.
In addition, an aqueous composition made by combining methyl celluloses with different specifications at a particular ratio is not known at all which has a function to protect the cornea or a function to mitigate corneal epithelium disorders by forming into gel around the body temperature.